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Biomedical subjects

R Mechoulam

Publications and source records attributed to R Mechoulam.

At least 109 records · Page 6Linked to original sources
PubMed1991

A random walk through a cannabis field.

The present overview covers various aspects of research going on in the Cannabis field in the Department of Natural Products at the Hebrew University. In the first part we discuss, and try to explain, the reason for the absence of the term Cannabis (and possibly also opium) in the Old Testament. In the second part we bring evidence that, contrary to widely held views, stereospecificity of cannabinoid action is extremely high, and in certain cases almost absolute. Previous results seem to have been due to impurities in the samples tested. (+)-Delta-1-THC, (+)-delta-6-THC and (+)-7-hydroxy-delta-6-THC, when purified sufficiently, exhibit activity of about 1% of that of the natural (-) enantiomers. A new labelled cannabinoid ligand has been prepared by catalytic reduction of (-)-7-hydroxy-delta-6-THC dimethylheptyl. The equatorial C-1 epimer obtained binds to the cannabinoid receptor with a KI of 40 pM. This compound is one of the most active cannabinoids tested so far for binding to the canabinoid receptor, and may become an important tool in cannabinoid research.

Cannabis↗
PubMed1991

Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs.

Numerous cannabinoids have been synthesized that are extremely potent in all of the behavioral assays conducted in our laboratory. An important feature in increasing potency has been the substitution of a dimethylheptyl (DMH) side chain for the pentyl side chain. Our previous studies have shown that (-)-11-OH-delta 8-THC-dimethylheptyl was 80-1150 times more potent than delta 9-THC. Stereospecificity was demonstrated by its (+)-enantiomer which was more than 1400-7500 times less potent. A related series of DMH cannabinoid analogs has recently been synthesized and preliminary evaluations reported here. (-)-11-OH-delta 9-THC-DMH was found to be equipotent with (-)-11-OH-delta 8-THC-DMH. The aldehyde (-)-11-oxo-delta 9-THC-DMH was 15-50 times more potent than delta 9-THC. Surprisingly, (-)-11-carboxy-delta 9-THC-DMH was also active, being slightly more potent than delta 9-THC. In the bicyclic cannabinoid series, the length and bulk of the side chain were found to be equally important. Aminoalkylindoles, which are structurally dissimilar from classical cannabinoids, have been found to exhibit a pharmacological profile similar to delta 9-THC. Though not extremely potent in vivo, they appear to represent an entirely new approach to studying the actions of the cannabinoids. The structural diversity and wide-ranging potencies of the analogs described herein provide the opportunity to develop a pharmacophore for the cannabinoids using molecular modeling techniques.

Analgesics↗
PubMed1991

Comparative metabolism of cannabidiol in dog, rat and man.

Urinary metabolites of cannabidiol (CBD) were extracted from human, dog and rat urine, concentrated by chromatography on Sephadex LH-20, and identified by GC/MS. Over 50 metabolites were identified with considerable species variation. CBD was excreted in substantial concentration from human urine, both in the free state and as its glucuronide. In dog, unusual glucoside conjugates of three metabolites (4''- and 5''-hydroxy and 6-oxo-CBD), not excreted in the unconjugated state, were found as the major metabolites at early times after drug administration. Other metabolites in all three species were mainly acids. Side-chain hydroxylated derivatives of CBD-7-oic acid were particularly abundant in human urine but much less so in dog. In the latter species the major oxidized metabolites were the products of beta-oxidation with further hydroxylation at C-6. A related, but undefined pathway, resulted in loss of three carbon atoms from the side-chain of CBD in man with the production of 2''-hydroxy-tris,nor-CBD-7-oic acid. Previous experiments indicate that 3'-hydroxy-metabolites are the precursors of compounds having this side-chain. Metabolism by the epoxide-diol pathway, resulting in dihydro-diol formation from the delta-8-double bond, gave metabolites in both dog and human urine. It was concluded that CBD could be used as a probe of the mechanism of several types of biotransformation, particularly those related to carboxylic acid metabolism, as intermediates of the type not usually seen with endogenous compounds were excreted in substantial concentration.

Animals↗
PubMed1991

Suppression of neuropathic pain behavior in rats by a non-psychotropic synthetic cannabinoid with NMDA receptor-blocking properties.

HU211 is a novel synthetic derivative of tetrahydro-cannabinol (THC), the active marijuana ingredient. The stereochemistry of HU211 is enantiomeric to that of THC. In contrast to THC, HU211 is not psychotropic. This agent exhibits other types of biological activities; it is a non-competitive NMDA receptor blocker and has antinociceptive activity when injected with cupric chloride. This study examined its effects in autotomy, a behavioral model of neuropathic pain. Autotomy, a behavior of self-mutilation of denervated areas, was induced in Sabra rats by cutting the sciatic and saphenous nerves. We found that injections of HU211 (2.5 mg/kg) with cupric chloride (0.8 mg/kg) every 2nd day markedly suppressed autotomy during the injection period by delaying its average onset day and reducing the incidence of severe autotomy. Moreover, suppression of autotomy was retained in the postinjection period (for at least 30 days) but only when the drug was injected intraperitoneally. Lesser effects were achieved by subcutaneous injections. Cupric chloride or HU211 alone were ineffective. The general behavior and open field motor activity indicated that the effects of HU211 with Cu++ on autotomy were not due to sedation or ataxia but presumably due to antinociception mediated by NMDA receptor blockade.

Animals↗
PubMed1990

Stereochemical effects of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl to inhibit adenylate cyclase and bind to the cannabinoid receptor.

The recent preparation of the enantiomers of 11-OH-delta 8-tetrahydrocannabinol-dimethylheptyl (THC-DMH), recrystallized to absolute enantiomeric purity, has made it possible to examine the requirement for stereospecificity for the interaction of this component with the cannabinoid receptor, defined by the binding of [3H]CP-55,940 and the adenylate cyclase enzyme. The enantiomer (-)11-OH-delta 8-THC-DMH exhibited a fully efficacious and potent (IC50 = 1.8 nM) inhibition of the accumulation of cAMP in intact N18TG2 cells. The (-)enantiomer was as efficacious and potent (Kinh = 7.2 nM) as desacetyllevonantradol in inhibiting adenylate cyclase activity in membrane preparations. The (-)enantiomer was able to compete fully for the specific binding of [3H]CP-55,940 to membranes from the brain of the rat in homologous displacement studies (Ki = 234 pM). The potency ratios exhibited by the (-) to (+)enantiomers of 11-OH-delta 8-THC-DMH exceeded 1000 for each of these activities.

Adenylyl Cyclase Inhibitors↗
PubMed1990

Cannabimimetic activity of novel enantiomeric, benzofuran cannabinoids.

The synthesis of the (2R,3R,4S,6R)-7/(2S,3S,4R,6S)-8 enantiomeric pair of benzofuran cannabinoids is reported together with the 1H and 13C NMR spectral parameters. In benzofuran 8 the configurational arrangement of ligated groups at the stereogenic C(3) atom (through which the terpene moiety is connected to the aromatic ring) is very similar to that of the corresponding atom in natural (3R,4R)-delta 1-tetrahydrocannabinol (delta 1-THC), although their respective Cahn-Ingold-Prelog descriptors are different. In drug-discrimination tests in pigeons and rats, benzofuran 8 is as active as delta 1-THC; in the mouse ring test compound 8 is more active than delta 6-THC. Enantiomer 7 is considerably less active than enantiomer 8 in both tests. These results can be explained by the fact that both 7 and 8 have a dimethylheptyl side chain (which is known to enhance cannabimimetic activity) and that delta 1-THC and benzofuran 8 have closely related conformations, as determined by molecular mechanics.

Animals↗
PubMed1990

Metabolites of cannabidiol identified in human urine.

1. Urine from a dystonic patient treated with cannabidiol (CBD) was examined by g.l.c.-mass spectrometry for CBD metabolites. Metabolites were identified as their trimethylsilyl (TMS), [2H9]TMS, and methyl ester/TMS derivatives and as the TMS derivatives of the product of lithium aluminium deuteride reduction. 2. Thirty-three metabolites were identified in addition to unmetabolized CBD, and a further four metabolites were partially characterized. 3. The major metabolic route was hydroxylation and oxidation at C-7 followed by further hydroxylation in the pentyl and propenyl groups to give 1"-, 2"-, 3"-, 4"- and 10-hydroxy derivatives of CBD-7-oic acid. Other metabolites, mainly acids, were formed by beta-oxidation and related biotransformations from the pentyl side-chain and these were also hydroxylated at C-6 or C-7. The major oxidized metabolite was CBD-7-oic acid containing a hydroxyethyl side-chain. 4. Two 8,9-dihydroxy compounds, presumably derived from the corresponding epoxide were identified. 5. Also present were several cyclized cannabinoids including delta-6- and delta-1-tetrahydrocannabinol and cannabinol. 6. This is the first metabolic study of CBD in humans; most observed metabolic routes were typical of those found for CBD and related cannabinoids in other species.

Biotransformation↗
PubMed1989

Inhibition of cisplatin-induced emesis in the pigeon by a non-psychotropic synthetic cannabinoid.

The (+) enantiomer of the synthetic cannabinoid, 7-hydroxy-delta-6-tetrahydrocannabinol, dimethylheptyl homolog (HU-211), possesses significant antimetic efficacy in the pigeon. However, unlike all anti-emetic cannabinoids tested in the past, it is devoid of psychotropic (cannabimimetic) activity. The anti-emetic activity of HU-211 was determined in pigeons given 10 mg/kg i.v. cisplatin, a widely used antitumour agent, which is also a potent emetogenic agent at this dose. This activity was compared with that of delta-1-tetrahydrocannabinol (delta-1-THC). HU-211 pretreatment elicited a dose-related inhibition of cisplatin vomiting, with the optimal dose of HU-211 (2.5 mg/kg) inhibiting emesis by nearly 90%. Delta-1-THC in doses up to 5 mg/kg caused only an insignificant reduction in vomiting. The activity was increased in the presence of cupric chloride (0.8 mg/kg). The optimal dose of delta-1-THC (5.0 mg/kg) with CuCl2 very significantly diminished the total amount of vomitus expelled (up to 90%). However, it failed to inhibit emesis in 50% of all animals tested, did not significantly affect the time of onset of emesis and was highly psychotropic. The optimal dose of HU-211 (2.5 mg/kg) with CuCl2 inhibited emesis by 97%, significantly delayed the time on onset of emesis in the very few animals that did vomit and was completely non-psychotropic. The curve for the antiemetic effect of HU-211 was U-shaped over a narrow dose range. The present report demonstrates that complete separation of psychotropic and antiemetic activities is possible in the cannabinoid series.

Animals↗
PubMed1989

Stereochemical effects of 11-OH-delta 8-THC-dimethylheptyl in mice and dogs.

The effects of the enantiomers of 11-hydroxy-delta 8-tetrahydrocannabinol-dimethylheptyl (11-OH-delta 8-THC-DMH) on spontaneous activity, rectal temperature, tail-flick latency, and catalepsy were studied in mice and in the dog static-ataxia model to determine the relative potency of each enantiomer. The (-)-enantiomer was active in all tests between 3-100 micrograms/kg, while the (+)-enantiomer was inactive at 30 mg/kg in the mouse and 1 mg/kg in the dog. The (-)-enantiomer was 100-800 times more potent than delta 9-THC in the mouse. The high degree of enantioselectivity and potency are suggestive of an interaction at a specific site such as a receptor.

Animals↗
PubMed1989

Nonpsychotropic cannabinoid acts as a functional N-methyl-D-aspartate receptor blocker.

Binding studies using the enantiomers of the synthetic cannabinoid 7-hydroxy-delta 6-tetrahydrocannabinol 1,1-dimethylheptyl homolog in preparations of rat brain cortical membranes reveal that the (+)-(3S,4S) enantiomer HU-211 blocks N-methyl-D-aspartate (NMDA) receptors in a stereospecific manner and that the interaction occurs at binding sites distinct from those of other noncompetitive NMDA antagonists or of glutamate and glycine. Moreover, HU-211 induces stereotype and locomotor hyperactivity in mice and tachycardia in rat, effects typically caused by NMDA receptor antagonists. HU-211 is also a potent blocker of NMDA-induced tremor, seizures, and lethality in mice. This compound may therefore prove useful as a nonpsychoactive drug that protects against NMDA-receptor-mediated neurotoxicity.

Animals↗
PubMed1989

Stereospecific effects of (-)- and (+)-7-hydroxy-delta-6-tetrahydrocannabinol-dimethylheptyl on the immune system of mice.

The effects of the (+) and (-) cannabinoid enantiomers 7-hydroxy-delta-6-tetra-hydrocannabinol-dimethylheptyl [(-)-7-OH-delta-6-THC-DMH (HU-210) and (+)-7-OH-delta-6-THC-DMH (HU-211)] on the inductive and productive phases of the primary humoral immune response to sheep red blood cell immunization were investigated in mice. Animals treated with (-)-7-OH-delta-6-THC-DMH (0.01, 0.05, 0.1 and 0.5 mg/kg) exhibited a dose-dependent suppression of both phases of the primary humoral immune response in the hemolytic plaque assay, the hemagglutination titer and in the ratio of the spleen weight to final body weight. Mice treated with (+)-7-OH-delta-6-THC-DMH (0.01, 0.05, 0.01, 0.5 and 1.0 mg/kg) did not exhibit dose-dependent immune suppression. However, the (+) enantiomer reduced the number of plaque-forming cells in the hemolytic plaque assay during the inductive phase. Mice treated with a combination of (-) and (+) enantiomers, each at 0.01 mg/kg, exhibited no impairment in ability to undergo a primary humoral immune response (inductive phase).

Animals↗
PubMed1989

Stereospecificity of the discriminative stimulus functions of the dimethylheptyl homologs of 11-hydroxy-delta 8-tetrahydrocannabinol in rats and pigeons.

Rats and pigeons were trained to discriminate between the presence and absence of the effects of (-)-delta 9-tetrahydrocannabinol (THC) at doses of 3 and 0.56 mg/kg, respectively; injections were i.p. and i.m., 0.5 and 1.5 hr before session onset for the two species, respectively. Tests with the 1,1 dimethylheptyl (DMH) homolog of (-)- delta 8-THC as well as its 11-hydroxylated (11-OH) derivative [(-)-11-OH-delta 8-THC-DMH], showed that both compounds were more potent than the training compound, especially so in the case of the 11-OH product (66 and 80 times more potent than delta 9-THC in rats and pigeons, respectively). The enantiomer, (+)-11-OH-delta 8-THC-DMH, was inactive as a THC-like psychotomimetic in doses even up to 10 mg/kg [ED50 of (-)-11-OH-delta 8-THC being 0.01 mg/kg and 0.002 mg/kg in rats and pigeons, respectively]. Hence, the typical THC-like effects in rats and pigeons (and by extrapolation possibly also the feeling of "high" in humans), reside exclusively in the levo [(-)]-enantiomers of THC-type cannabinoids (at least in the pair studied by us) as demonstrated clearly in this study. Both (-)-delta 8-THC-DMH and (-)-11-OH-delta 8-THC-DMH had a slow onset and a long duration of action.

Animals↗
PubMed1988

Separation of the discriminative stimulus effects of stereoisomers of delta 2- and delta 3-tetrahydrocannabinols in pigeons.

Pigeons, trained to discriminate between the presence or absence of delta 1-tetrahydrocannabinol (THC) (I) (0.56 mg/kg), were tested with (1S,4R)-delta 2-THC (II) (1-17.5 mg/kg), with the C-1 epimers of (4R)-delta 2-THC acetate, namely (1S,4R)-delta 2-THC acetate (IIIA) (3-17.5 mg/kg) and (1R,4R)-delta 2-THC acetate (IIIB) (1-17.5 mg/kg) and with the enantiomers of delta 3-THC acetate, namely (1S)-delta 3-THC acetate (IVA) (1-10 mg/kg) and (1R)-delta 3-THC acetate (IVB) (3-30 mg/kg). The results indicated that (I) was considerably more potent than any of the other compounds evaluated (ED50 of compound I = 0.18 and 0.25 mg/kg at the two post-injection intervals examined, 90 and 270 min, respectively). Furthermore, of the two delta 2-THC acetates, compound (IIIB) was active whereas compound (IIIA) was not in comparable doses. The parent phenol of compound (IIIA), namely (II), was also inactive. Comparison of the pair of enantiomers, (IVA) and (IVB), showed the former to be significantly more potent than the latter. We have thus shown that the delta 1-THC-like cue properties are separated in the stereoisomers of delta 2- and delta 3-THC.

Animals↗
PubMed1988

Enantiomeric cannabinoids: stereospecificity of psychotropic activity.

The 1,1-dimethylheptyl homolog of (-)-(3R,4R)-7-hydroxy-delta-6- tetrahydrocannabinol (compound II) is highly psychotropic in mice, rats and pigeons. The (+)-(3S,4S) enantiomer (III) was found to be psychotropically inactive at doses up to several thousand times those of the ED50 of (II).

Animals↗
PubMed1987

Human pharmacology of 1S and 1R enantiomers of delta-3-tetrahydrocannabinol.

Two enantiomers (1S and 1R) of delta-3-tetrahydrocannabinol were assayed in man for psychoactivity. The 1S enantiomer had definite psychic actions, qualitatively similar to those of delta-1-tetrahydrocannabinol, but quantitatively less potent (1:3 to 1:6). Adding the two enantiomers together did not increase the effect, confirming that activity was solely in the one enantiomer and that there was no interaction between them.

Adult↗
PubMed1987

Anticonvulsant and neurotoxic effects of tetrahydrocannabinol stereoisomers.

Enantiomers of delta-6-tetrahydrocannabinol (THC), delta-6-THC-1'', 1''-dimethylheptyl (DMHP), and 7-OH-delta-6-THC-1'',1''-DMHP were assessed for their ability to block audiogenic seizures in genetically epilepsy-prone rats. The stereoisomers were evaluated also for their ability to produce differential neurotoxicity in the rat rotorod (ROT) paradigm. Potency comparisons among the compounds revealed modest to profound stereoselectivity for anticonvulsant and neurotoxic activities, a general increase in both activities with the DMHP and 7-OH modifications of delta-6-THC, and some favorable separation between anticonvulsant and neurotoxic activities with selected THC analogs.

Animals↗